Back to EveryPatent.com
United States Patent |
5,043,152
|
Schaefer
,   et al.
|
August 27, 1991
|
Novel iodinated non-ionic triiodobenzene compounds and contrast media
containing them
Abstract
The invention relates to novel non-ionic compounds of formula
##STR1##
These compounds can be used as contrast media.
Inventors:
|
Schaefer; Michel (Chilly-Mazarin, FR);
Dugast-Zrihen; Maryse (Paris, FR);
Guillemot; Michel (Paris, FR);
Doucet; Didier (Livry-Gargan, FR);
Meyer; Dominique (Paris, FR)
|
Assignee:
|
Guerbet S.A. (Villepinte, FR)
|
Appl. No.:
|
480980 |
Filed:
|
February 16, 1990 |
Foreign Application Priority Data
| Jun 02, 1988[FR] | 88 07369 |
| Jan 23, 1989[FR] | 89 00762 |
| Jan 05, 1990[FR] | 90 00106 |
Current U.S. Class: |
424/9.454; 564/153; 564/156 |
Intern'l Class: |
A61K 049/04 |
Field of Search: |
564/153,156
424/5
|
References Cited
U.S. Patent Documents
3701771 | Oct., 1972 | Almen et al. | 564/153.
|
4364921 | Dec., 1982 | Speck et al. | 564/153.
|
4396598 | Aug., 1983 | Lin | 424/5.
|
4474747 | Oct., 1984 | Dimo et al. | 424/5.
|
Foreign Patent Documents |
0345163 | Jun., 1989 | EP.
| |
3429949 | Feb., 1986 | DE | 564/153.
|
Primary Examiner: Raymond; Richard L.
Assistant Examiner: Rand; Scott C.
Attorney, Agent or Firm: Young & Thompson
Parent Case Text
The present application is a continuation-in-part of U.S. Ser. No. 360,203
filed 6-1-89, now abandonded.
Claims
We claim:
1. A compound of the formula:
##STR27##
in which R.sub.1 is selected from a group of the formula
##STR28##
in which R.sub.5 is selected from C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4
hydroxyalkyl and C.sub.1 -C.sub.4 polyhydroxyalkyl, and
R.sub.6 is selected from hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4
hydroxy alkyl and C.sub.1 -C.sub.4 polyhydroxyalkyl,
and a group of the formula
##STR29##
in which R.sub.7 is selected from C.sub.1 -C.sub.4 hydroxyalkyl and
C.sub.1 -C.sub.4 polyhydroxyalkyl, and
R.sub.8 is selected from hydrogen and C.sub.1 -C.sub.4 alkyl,
R.sub.2 is selected from C.sub.1 -C.sub.4 hydroxyalkyl and C.sub.1 -C.sub.4
polyhydroxyalkyl,
R.sub.3 is selected from hydrogen and C.sub.1 -C.sub.4 alkyl, and
R.sub.4 is selected from hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4
hydroxyalkyl and C.sub.1 -C.sub.4 polyhydroxyalkyl.
2. A compound according to claim 1, having the formula:
##STR30##
in which R.sub.2, R.sub.3 and R.sub.4 have the meanings given in claim 1.
3. A compound according to claim 1 which is
5-[3-hydroxy-2-(hydroxymethyl)-N-(2,3-dihydroxypropyl)propionamido]-N',N"-
bis-(2-hydroxyethyl)-2,4,6-triiodoisophthalamide.
4. A compound according to claim 1 which is
5-glycolamido-3-[3-hydroxy-2-(hydroxymethyl)-N-(2,3-dihydroxypropyl)propio
namido]-2,4,6-triiodo-N-hydroxyethyl benzamide.
5. A compound according to claim 1 which is
3,5-bis-(3-hydroxy-2-hydroxymethyl-propionamido-2,4,6-triiodo-N-(2,3-dihyd
roxypropyl) benzamide.
6. A compound according to claim 1 which is
5-[3-hydroxy-2-(hydroxymethyl)-N-(2-hydroxyethyl)-propionamido]-N-(2-hydro
xyethyl)-N'-(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide.
7. A compound according to claim 1 which is
5-[3-hydroxy-2-(hydroxymethyl)-propionamido]-N',
N"-dimethyl]-N',N"-bis-(2,3-dihydroxypropyl)-2,4,6-triiodoisophtalamide.
8. A compound according to claim 1 which is
5-[3-hydroxy-2(hydroxymethyl)-N-(2,3-dihydroxypropyl)-propionamido]-N',N"-
dimethyl-N',N"-bis(2-hydroxyethyl)-2,4,6-triiodoisophtalamide.
9. A contrast medium comprising an effective amount of at least one
compound according to claim 1, in admixture with a pharmacologically
acceptable excipient, said amount being effective to provide contrast
during radiography.
10. A contrast medium according to claim 9, comprising an aqueous solution
of the compound(s).
11. A compound of the formula:
##STR31##
in which R.sub.1 is selected from a group of the formula
##STR32##
in which R.sub.5 is selected from C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4
hydroxyalkyl and C.sub.1 -C.sub.4 polyhydroxyalkyl, and
R.sub.6 is selected from hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4
hydroxyalkyl and C.sub.1 -C.sub.4 polyhydroxyalkyl;
and a group of the formula
##STR33##
in which R.sub.7 is selected from C.sub.1 -C.sub.4 hydroxyalkyl and
C.sub.1 -C.sub.4 polyhydroxyalkyl, and
R.sub.8 is selected from hydrogen and C.sub.1 -C.sub.4 alkyl,
R.sub.2 is selected from hydrogen, C.sub.1 -C.sub.4 hydroxyalkyl and
C.sub.1 -C.sub.4 polyhydroxyalkyl,
R.sub.3 is selected from hydrogen and C.sub.1 -C.sub.4 alkyl, and
R.sub.4 is selected from hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4
hydroxyalkyl and C.sub.1 -C.sub.4 polyhydroxyalkyl.
12. A contrast media comprising an effective amount of at least one
compound according to claim 11, in admixture with a pharmacologically
acceptable excipient, said amount being effective to provide contrast
during radiography.
Description
The present invention relates to compounds which can be used in contrast
media for radiography.
Iodobenzene compounds containing several iodine atoms in the benzene
nucleus, usually 3 iodine atoms per benzene nucleus, and various other
substituents have been used for a long time as contrast medium. These
other substituents are pharmacologically acceptable groups which enable
the compounds to be administered to man and animals. Generally speaking,
these substituents are chosen, on the one hand, in order to confer
adequate solubility in water on the compound so that they can be
administered in aqueous solution and, on the other, in order to confer on
these compounds sufficient tolerance for them to be tolerated by the human
organism.
For this purpose, non-ionic structures have been suggested, i.e.
iodobenzene derivatives possessing non-ionic substituents.
Thus, in the patent FR-A-2 053 037, carbamoyl iodobenzene compounds
containing a total of at least one N-hydroxy alkyl group and at least two
hydroxy groups were suggested.
A compound illustrative of this class is metrizamide which has, however,
proved to be of limited stability.
The present invention aims to provide novel non-ionic compounds which are
well tolerated by the human organism, very stable in aqueous solution,
which possess a high solubility in water and which exhibit low viscosity
in solution.
To this end, the subject of the present invention is compounds of formula:
##STR2##
in which R.sub.1 is selected from a group of formula
##STR3##
in which R.sub.5 is selected from C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4
hydroxyalkyl or C.sub.1 -C.sub.4 polyhydroxyalkyl, and
R.sub.6 is selected from hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4
hydroxyalkyl or C.sub.1 -C.sub.4 polyhydroxyalkyl,
and a group of formula
##STR4##
in which R.sub.7 is selected from C.sub.1 -C.sub.4 hydroxyalkyl or C.sub.1
-C.sub.4 polyhydroxyalkyl, and
R.sub.8 is selected from hydrogen or C.sub.1 -C.sub.4 alkyl,
R.sub.2 is selected from hydrogen, C.sub.1 -C.sub.4 hydroxyalkyl or C.sub.1
-C.sub.4 polyhydroxyalkyl,
R.sub.3 is selected from hydrogen or C.sub.1 -C.sub.4 alkyl, and
R.sub.4 is selected from hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4
hydroxyalkyl or C.sub.1 -C.sub.4 polyhydroxyalkyl.
In the present invention by polyhydroxyalkyl group is meant a linear or
branched polyhydroxyalkyl group.
A preferred compound of formula I is the compound of formula I in which
R.sub.1 =--CO--NH--CH.sub.2 --CH.sub.2 OH,
R.sub.2 =--CH.sub.2 --CH.sub.2 OH,
R.sub.3 =H
R.sub.4 =--CH.sub.2 --CHOH--CH.sub.2 OH.
Moreover, a preferred group of compounds of formula I is that constituted
by the compounds of the symmetrical diamino type, i.e. the compounds of
formula:
##STR5##
the compounds of formula I can be prepared in a standard manner in
particular by acylation and/or alkylation reactions starting from known
compounds.
Thus, the compounds of the symmetrical diamino type (compounds of formula
II) can be prepared by
a) acylation of a diamino compound of formula:
##STR6##
R.sub.2 ' representing a R.sub.2 group, the hydroxy groups of which have
been protected, with an acid chloride of formula:
RCOCl IV
in which R represents
##STR7##
the hydroxy groups of which are protected, b) alkylation of the compound
obtained, if necessary, with an alkylating reagent of formula:
R'.sub.4 Z V
in which R'.sub.4 has the meanings given previously except hydrogen and Z
represents a labile group such as an atom of chlorine, bromine or iodine,
in the presence of a base such as sodium methylate, sodium ethylate,
sodium hydride or sodium hydroxide.
c) deprotection
Compounds of formula III are described in the French patent application
FR-A-2 614 299.
The other compounds of formula III can be prepared in an analogous manner
starting in particular from an alkyl 3,5-dinitrobenzoate of formula:
##STR8##
in which R' is a C.sub.1 -C.sub.4 alkyl group such as methyl.
Asymmetric diamino compounds can also be prepared starting from a compound
of formula VI by:
a) reaction with an amine of formula:
##STR9##
so as to produce a compound of formula:
##STR10##
b) reduction by means of ammonium sulfide so as to give rise to a compound
of formula:
##STR11##
c) acylation of the compound of formula IX by an acid chloride of formula
RCOCl (IV) so as to give rise to a compound of formula:
##STR12##
d) reduction and iodination of the compound of formula X so as to give
rise to a compound of formula:
##STR13##
e) alkylation, if required, of the compound of formula XI with an
alkylating reagent of formula V so as to give rise to a compound of
formula:
##STR14##
f) deprotection of the compound of formula XII g) acylation of the
deprotected compound obtained with an acid chloride of formula:
Cl--CO--R'.sub.5 XIII
R'.sub.5 representing a group R.sub.5, the hydroxy groups of which are
protected, so as to give rise after deprotection to a compound of formula:
##STR15##
the steps f and g may be carried out in the reverse order, and if
necessary
h) alkylation to give rise to a compound of formula I in which R.sub.6 has
the meanings indicated except hydrogen.
Symmetrical compounds of the isophthalic type (compounds of formula I in
which
##STR16##
can be prepared by a) acylation of an amine of formula:
##STR17##
with an acid chloride of formula RCOCl (IV) so as to give rise to a
compound of formula:
##STR18##
b) reaction of the compound of formula XVI with an amine of formula
##STR19##
so as to give rise to a compound of formula:
##STR20##
then, if desired, either c) alkylation of the compound of formula XVII
with an alkylating reagent of formula R'.sub.4 Z such as that specified
previously and finally
d) removal of the protecting groups from the --CH(CH.sub.2 OH).sub.2 group,
or
e) removal of the protecting groups from the --CH(CH.sub.2 OH).sub.2 group
and, if desired,
f) alkylation of the deprotected compound with an alkylating reagent
R'.sub.4 Z.
The asymmetric compounds of the isophthalic type (compounds of formula I in
which
##STR21##
with R.sub.7 .noteq.R.sub.2 and/or R.sub.8 .noteq.R.sub.3) can be prepared
by
a) acylation of an amine of formula
##STR22##
with an acid chloride of formula RCOCl, b) alkylation, if desired, with
an alkylating reagent of formula R'.sub.4 Z and
c) removal of the protecting groups from the --CH--(CH.sub.2 OH).sub.2
group.
The compound of formula XVIII may be obtained as described in EP--0 015
867.
As an alternative, the asymmetric compounds of the isophthalic type can be
prepared by
a) acylation of an amine of formula:
##STR23##
in which R'.sub.7 represents a R.sub.7 group in which the hydroxy groups
are protected,
with an acid chloride of formula RCOCl (IV) so as to give rise to a
compound of formula:
##STR24##
b) reaction of the compound of formula XX with an amine of formula:
##STR25##
so as to give to a compound of formula:
##STR26##
then, if desired, either c) alkylation of the compound of formula XXI
with an alkylating reagent of formula R'.sub.4 Z such as that previously
specified and finally
d) removal of the protecting groups from the --CH--(CH.sub.2 OH).sub.2
group, or
e) removal of the protecting groups from the --CH--(CH.sub.2 OH).sub.2
group, and, if desired,
f) alkylation of the deprotected compound with an alkylating reagent
R'.sub.4 Z.
Another subject of the present invention is contrast medium, which contain
at least one compound of formula I.
These contrast media are used in man and animals for radiological purposes.
The preferred pharmaceutical form of the contrast materials according to
the invention consists of aqueous solutions of the compounds.
The aqueous solutions usually contain a total of from 5 to 100 g of
compounds of formula I per 100 ml and the volume of such solution to be
injected usually varies from 1 to 1000 ml.
The aqueous solution of the compounds of formula I may also contain certain
additives such as:
sodium chloride at concentrations included between 0.1 and 10 mM/l
disodium EDTA at concentrations included between 0.1 and 2 mM/l
sodium citrate at concentrations included between 0.1 and 10 mM/l
heparin at doses included between 10 and 100 units per 100 ml of solution.
These compounds may be administered by all routes conventionally used for
iodinated non-ionic contrast medium Thus, they may be administered by the
enteral route or the parenteral route (intravenous route, intra-arterial
route, opacification of the cavities) and in particular into the
subarachnoid space.
An example of the composition according to the present invention will be
given below.
______________________________________
Composition
______________________________________
Composition of example 1 65 g
Water for injectable preparation
QS 100 ml
______________________________________
The following examples illustrate the preparation of the compounds of
formula I.
Example 1
Preparation of
5-[3-hydroxy-2-(hydroxymethyl)-N-(2,3-dihydroxypropyl)propionamido]-N',N"-
bis-(2-hydroxyethyl)-2,4,6-triiodo-isophthalamide
a) Preparation of
5-[2-isopropyl-1,3-dioxane-5-carboxamido]-2,4,6-triiodo-isophthaloyl
dichloride
137 g of 5-amino-2,4,6-triiodoisophthaloyl chloride (0.23 mole) are
dissolved in 460 ml of DMAC to which are added 110 g (0.57 mole) of
2-isopropyl-1,3-dioxane-5-carboxylic acid chloride. The reaction mixture
is stirred under argon at ambient temperature for 4 days. The DMAC is
removed in a vacuum. The oil obtained is extracted with 3 l of ethyl
acetate and washed twice with 1 l of ice-cold water. The organic phase is
dried and concentrated to dryness. The product is crystallized from 200 ml
of CH.sub.2 Cl.sub.2. After filtration, 110 g of solid are obtained:
______________________________________
Yield: 64%
TLC: SiO.sub.2 CH.sub.2 Cl.sub.2
Rf: 0.13
(6O F 254) SiO.sub.2 ether/petroleum ether 50/50
Rf: 0.52
______________________________________
b) Preparation of
5-[2-isopropyl-1,3-dioxane-5-carboxamido]-N',N"-bis-(2-hydroxyethyl)-2,4,6
-triiodo-isophthalamide
130 g of the product obtained in a (0.173 mole) are dissolved in a solution
of 750 ml of DMAC and 75 ml (0.534 mole) of triethylamine. 33.7 g of
ethanolamine (0.552 mole) are added dropwise to the reaction mixture. The
reaction mixture is then stirred for 3 hours at ambient temperature. The
triethylamine hydrochloride is removed by filtration and the DMAC is
removed in a vacuum. The oil obtained is crystallized from 1 liter of
water. The product is filtered off and dried in a vacuum.
______________________________________
Yield: 95%
TLC: SiO.sub.2 Rf: 0.25
CH.sub.2 Cl.sub.2 /methanol 9/1
(60F254) SiO.sub.2 Rf: 0.67
CH.sub.2 Cl.sub.2 /methanol 8/2
% I: 45.6 (found) - 47.6 (theory)
Hypersil C8 5.mu. 15 cm
HPLC purity: 97% 0.01M NaH.sub.2 PO.sub.4 = 50
Methanol = 50
______________________________________
c) Preparation of
5-[3-hydroxy-2-hydroxymethyl-N-(2,3-dihydroxypropyl)propionamido]-N',N"-bi
s-(2-hydroxyethyl)-2,4,6-triiodo-isophthalamide
To a suspension of 100 g of the product obtained in b (0.125 mole) in 350
ml of ethylene glycol are added dropwise 125 ml (0.5 mole) of 4N methylate
at 60.degree. C. followed by 65 g (0.625 mole) of
1-chloro-2,3-propanediol. After 1 hour at 60.degree. C. the mass of the
reaction mixture has increased. 100 ml (0.4 mole) of 4N methylate and 55.2
g (0.5 mole) of 1-chloro-2,3-propanediol are added. The mixture is
maintained overnight at 60.degree. C. A further addition of 31 ml (0.125
mole) of 4N methylate and 20.7 g of 1-chloro-2,3-propanediol is made.
Stirring is maintained for 4 hours at 60.degree. C. The mineral salts are
removed by filtration. The ethylene glycol is evaporated in a vacuum.
The distillation residue is taken up in 800 ml of 10N HCl and the solution
is stirred overnight at ambient temperature. The reaction mixture is
concentrated to dryness and the residue is taken up in 300 ml of ethanol.
The mineral salts are removed by filtration. The ethanol is evaporated in
a vacuum and the residue is crystallized from 1 liter of isopropyl
alcohol. The precipitate is filtered off and purified by HPLC (RP 18)
(elution with water).
______________________________________
Total yield (alkylation-deprotection-purification): 52%
(1) TLC (silica 60F254): CH.sub.2 Cl.sub.2 /methanol 7/3 Rf: 0.4
(2) HPLC Hypersil C8 5.mu. 15 cm
Buffer 0.01M NaH.sub.2 PO.sub.4
97
methanol 3
Purity: 97%
(3) % I: 45.8 (found) - 46.4 (theory)
(4) NMR (DMSO)
______________________________________
Poorly resolved multiplet centered at 3.5 ppm (18H); multiplet centered at
4.5 ppm (OH) exchangeable with D.sub.2 O (6 H); broad peak at 8.4 ppm (NH)
exchangeable with D.sub.2 O (2 H).
EXAMPLE 2
Preparation of
5-qlycolamido-3-[3-hydroxy-2-hydroxymethyl-N-(2,3-dihydroxypropyl)propiona
mido]-2,4,6-triiodo-N-hydroxyethyl benzamide
a) Preparation of 3,5-dinitro-N-(2-hydroxyethyl)benzamide
750 g (3.32 moles) of methyl 3,5-dinitro benzoate are suspended in 2 liters
of methanol in the presence of 222.7 g (3.65 moles) of ethanolamine. The
reaction mixture is refluxed for 48 hours until the ester has disappeared.
After 4 hours at room temperature, the crystalline product is filtered
off, washed with 500 cm.sup.3 of methylene chloride, then dried in an oven
at 60.degree. C. in a vacuum for 4 hours. This procedure leads to the
recovery of 718 g of product in a yield of 85% Melting point: 140.degree.
C.
TLC (toluene/methyl ethyl ketone/formic acid (60/25/25) Rf: 0.5.
b) Preparation of 3-nitro 5-amino-N-(2-hydroxyethyl)benzamide
To a suspension of 25.5 g (0.5 mole) of
3,5-dinitro-N-(2-hydroxyethyl)benzamide in 135 cm.sup.3 of water are added
at 70.degree. C. 12.25 g (0.18 mole) of ammonium sulfide. At the end of
the addition the mixture is homogenous but reprecipitation occurs after
1/2 hour at 70.degree. C. The reaction mixture is allowed to cool to
ambient temperature and stirring is continued for 2 hours. The precipitate
is filtered off, washed with methanol (70 cm.sup.3) then dried in an oven
(60.degree. C.).
Mass obtained: 15.1 g --yield 67%.
TLC (toluene/methyl ethyl ketone/formic acid 60/25/25). Rf: 0.3
.sup.1 H NMR (DMSO): 3.4 ppm (multiplet; 4H,CH.sub.2 aliphatics); 4.65 ppm
(multiplet, H exchangeable with D.sub.2 O, NH.sub.2); 5.9 ppm (singlet, H
exchangeable with D.sub.2 O, OH); 7.4-7.7 ppm (2 multiplets; 3H, aromatic
protons); 8.6 ppm (multiplet, 1H, NH).
c) Preparation of
3-nitro-5-[2-isopropyl-1,3-dioxane-5-carboxamido]-N-hydroxyethyl benzamide
40 g (0.177 mole) of 3-nitro-5-amino-N-(2-hydroxyethyl)benzamide are
dissolved in 400 cm.sup.3 of DMAC. The addition of 74.9 g (0.389 mole) of
2-isopropyl-1,3-dioxane-5-carboxylic acid chloride in the presence of
triethylamine (54.6 cm.sup.3) gives rise to an exothermic reaction.
The reaction mixture is maintained under argon for 18 hours at ambient
temperature. The mixture is filtered and the filtrate is diluted with
water and extracted with ethyl acetate. The residue obtained after
evaporation of the solvent is treated with potassium carbonate (12 g) in
300 cm.sup.3 of methanol. After being stirred at ambient temperature for
48 hours, the mixture is concentrated, then extracted with ethyl acetate.
The crude product obtained after treatment is recrystallized from a
mixture of ether/ethyl acetate 80/20. 37.8 g of product are isolated in a
yield of 56%.
______________________________________
TLC (ethyl acetate Rf: 0.48). -HPLC Hypersil C8 5.mu. 15 cm.
Buffer: 0.01M
NaH.sub.2 PO.sub.4
50%
MeOH 50%
Purity: 94%.
______________________________________
d) Preparation of
5-amino-3-[2isopropyl-1,3-dioxane-5-carboxamido]-2,4,6-triiodo-N-hydroxyet
hyl-benzamide
A methanolic solution (1.4 l) of 40 g of
3-nitro-5-[2-isopropyl-1,3-dioxane-5-carboxamido]-N-hydroxyethyl benzamide
is stirred under an atmosphere of hydrogen (5.10.sup.5 Pa) for 5 hours at
50.degree. C. in the presence of 4 g of palladized charcoal. The catalyst
is then filtered off and the filtrate is evaporated under reduced
pressure. The resulting compound is suspended in 950 cm.sup.3 of water.
The mixture is made homogenous by the addition of 20 cm.sup.3 of 2N
hydrochloric acid. 63 cm.sup.3 of iodine chloride (70% in iodine) are then
added dropwise with vigorous stirring. After 24 hours at ambient
temperature, the precipitate is filtered off, washed with water, taken up
in ether. After drying, 32 g of product are obtained in a yield of 42%.
TLC (dichloromethane/methanol 90/10) Rf: 0.8.
e) Preparation of
5-amino-3-[N-(2,3-dihydroxypropyl)-2-isopropyl-1,3-dioxane-5-carboxamido]-
2,4,6-triiodo-N-hydroxyethyl benzamide
To a solution of the compound obtained in d) (20 g, 0.027 mole) in a
mixture of ethylene glycol-dimethylformamide v/v (160 ml) are added
dropwise 84 cm.sup.3 (0.337 mole) of 4N sodium methylate. The mixture is
heated at 60.degree. C. for 1/2 hour and 36.1 cm.sup.3 (0.432 mole) of
1-chloro-2,3-propanediol are added at this temperature. The reaction
mixture is maintained at 60.degree. C. under nitrogen for 60 hours. The
mineral salts are removed by filtration. The ethylene glycol and the DMF
are evaporated in a vacuum. The crude product obtained is purified on
silanized silica (elution with water, followed by water/methanol 50/50).
16.5 g of product are isolated. Yield 76%.
TLC (dichloromethane/methanol 80/20). Rf: 0.8.
f) Preparation of 5-amino
3-[3-hydroxy-2(hydroxymethyl)-N-(2,3-dihydroxypropyl)propionamido]-2,4,6-t
riiodo-N-hydroxyethyl benzamide
16 g (0.02 mole) of the product obtained in e) are deprotected in the
presence of 80 cm.sup.3 of 10N hydrochloric acid for 48 hours at ambient
temperature. After neutralization and evaporation under reduced pressure,
the residue is precipitated with a mixture of methanol-ether (9/1),
filtered off then purified by HPLC (RP 18) (elution with water then with
water/methanol 90/10).
4 g of product are isolated in an overall yield (deprotection,
purification) of 30%.
______________________________________
TLC (dichloromethane/methanol 80/20). Rf: 0.25.
HPLC Hypersil C8 5.mu. 15 cm.
Buffer: 0.01M
NaH.sub.2 PO.sub.4
90%
MeOH 10%
Purity: 97%.
______________________________________
g) Preparation of
5-N-qlycolamido-3-[3-hydroxy-2(hydroxymethyl)-N-(2,3-dihydroxypropyl)propi
onamido]-2,4,6-triiodo-N-hydroxyethyl benzamide
5.5 g of 0-acetylated glycolic acid chloride (0.04 mole) are added dropwise
at ambient temperature to a solution of 3 g of the compound obtained in
step f (0.004 mole) in 30 cm.sup.3 of anhydrous DMAC. The reaction mixture
is heated at 40.degree. C. for 12 hours, then poured into 250 cm.sup.3 of
ice-cold water. The precipitate obtained is filtered off then extracted
with ethyl acetate. After treatment followed by evaporation, the product
obtained dissolved in 50 cm.sup.3 of methanol is deprotected in the
presence of 10 cm.sup.3 of 1N sodium hydroxide. The solution is stirred at
ambient temperature for 14 hours, then desalted by successive passages
through H.sup.+ (IRN77) and OH.sup.- (IRN78) resins. After evaporation to
dryness, the residue is taken up in ethyl ether, filtered then dried.
Mass obtained: 1.5 g. Overall yield: 47%.
Purity in iodine: 99%.
______________________________________
TLC (ethyl acetate/methanol/ammonia 60/40/1).
Rf: 0.25.
HPLC Hypersil C8 5.mu. 15 cm.
Buffer: 0.01M
NaH.sub.2 PO.sub.4
90%
Me OH 10%
Purity: 89%
______________________________________
EXAMPLE 3
Preparation of
3,5-bis-(3-hydroxy-2-hydroxymethyl-propionamido)-2,4,6-triiodo-N-(2,3-dihy
droxypropyl)benzamide
a) Preparation of
3,5-diamino-2,4,6-triiodo-N-(2,3-diacetoxypropyl)benzamide
301.5 g (0.5 mole) of
3,5-diamino-2,3,6-triiodo-N-(2,3-dihydroxypropyl)benzamide are suspended
in 1 l of anhydrous pyridine cooled to 15.degree. C. After the addition of
2450 ml of acetic anhydride, the solution is stirred for 18 h at ambient
temperature, then poured into acidulated water. After extraction with
ethyl acetate, drying of the organic phase and evaporation, 270 g of
product are obtained in a yield of 78.5%.
Purity in iodine: 98.3%.
TLC toluene/methylethylketone/HCOOH 60/25/35. Rf: 0.70.
b) Preparation of
3,5-bis(2-isopropyl-1,3-dioxane-5-carboxamido)2,4,6-triiodo-N-(2,3-diaceto
xypropyl)benzamide
114.5 g (0.166 mole) of the compound obtained in a) are dissolved in 350 ml
of anhydrous DMAC. The addition of 128 g (0.66 mole) of
2-isopropyl-1,3-dioxane-5-carboxylic acid chloride is carried out at
0.degree. C. After being stirred overnight the reaction mass is poured
into a mixture of ice-water. The precipitate is filtered off, washed with
water then dried in a vacuum at 50.degree. C.
c) Preparation of
3,5-bis(2-isopropyl-1,3-dioxane-5-carboxamido)-2,4,6-triiodo-N(2,3-dihydro
xypropyl) benzamide
175 g of the compound obtained in b) suspended in 2.5 l of methanol are
stirred at ambient temperature in the presence of 45 g of potassium
carbonate overnight. After evaporation of the reaction mixture, the
product crystallizes from water. After filtration and drying, the crystals
obtained in 85% yield are used directly in the next step.
d) Preparation of 3,5-bis(3-hydroxy-2-hydroxymethyl
propionamido)-2,4,6-triiodo-N-(2,3-dihydroxypropyl)benzamide
The compound obtained in c) is dissolved in 2 l of 5N HCl at 50.degree. C.
After being stirred for 18 h, the suspension obtained is filtered. The
filtrate is concentrated in a vacuum and the residue is taken up in
isopropanol.
108 g of crystalline product are obtained in 2 crops in a yield of 94%.
TLC SiO.sub.2 Butanol 60, water 25, CH.sub.3 COOH 11: Rf: 0.2.
The product is purified by preparative HPLC on SiO.sub.2 RP18 15,25 u with
water as eluant in a yield of 47%.
Purity in iodine: 99.6%.
HPLC purity: 99.1% (Hypersil C8 5.mu. 15 cm 0.01M NaH.sub.2 PO.sub.4 95,
MeOH 5).
.sup.1 H NMR 200 MHz (DMSQ): 8.5 ppm (m,1H exchangeable with D.sub.2 O,
O-CONH); 9.9 ppm (t,2H exchangeable with D.sub.2 O, O-NH-CO); 4.6 ppm
(m,6H exchangeable, OH); 3-4 ppm (m, 13H, CH); 2.7 ppm (m, 2H,
NH--CH.sub.2).
EXAMPLE 4
Preparation of
5-[3-hydroxy-2-(hydroxymethyl)-N-(2-hydroxyethyl)propionamido]-N-(2-hydrox
yethyl)-N'-(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide
a) Preparation of
5-(2-isopropyl-1,3-dioxane-5-carboxamido)-2,4,6-triiodo-3-N'-(2-acetoxyeth
yl) carbamoyl-benzoyl chloride
5.36 g of 2-isopropyl-1,3-dioxane-5-carboxylic acid (0.0308 mole) are
dissolved in 18 ml of DMAC. The reaction mixture is cooled to 5.degree. C.
and 2.55 ml (0.0350 mole) of SOCl.sub.2 are added dropwise such that the
temperature remains below 15.degree. C. When the addition is complete, the
reaction mixture is left for 3 hours at ambient temperature.
Then 6.0 g (0.00906 mole) of 5-amino-2,4,6-triiodo-3-(N-2-acetoxyethyl)
carbamoyl-benzoyl chloride are added. The reaction mixture is maintained
under argon for 4 days at ambient temperature.
The DMAC is removed in a vacuum. The oil obtained is taken up in ethyl
acetate; the organic phase is washed with water, dried and concentrated to
dryness. The product is crystallized from 100 ml of ether. After being
filtered off and dried, 1.8 g of product are obtained in a yield of 24%.
TLC (silica 60F 254): ethyl acetate/petroleum ether 80/20-Rf=0.83.
b) Preparation of
5-(2-isopropyl-1,3-dioxane-5-carboxamido)-2,4,6-triiodo-N-(2-acetoxyethyl)
-N'-(2,3-dihydroxypropyl)isophthalamide
1 g (0.00122 mole) of the product obtained in a is dissolved in 100 ml of
DMAC, then 0.26 ml of triethylamine (0.00189 mole) are added. 0.18 g
(0.00196 mole) of 3-amino-1,2-propanediol are added dropwise to the
reaction mixture. After the addition is complete, the reaction mixture is
stirred under argon at ambient temperature for 24 hours.
The triethylamine hydrochloride is filtered off, then the DMAC is
evaporated. The oil thus obtained is crystallized from 20 ml of ether.
After being filtered off and dried, 0.8 g of product are obtained in a
yield of 75.5%.
TLC (silica 60F254): CHCl.sub.3 /MeOH/NH.sub.4 OH 53/30/10 Rf=0.77.
c) Preparation of
5[3-hydroxy-2-(hydroxymethyl)-N-(2-hydroxyethyl)propionamido]-N-(2-hydroxy
ethyl)-N'-(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide
0.4 g (0.000458 mole) of the product obtained in b are dissolved in 0.7 ml
of ethylene glycol and 0.69 ml (0.00275 mole) of a 4N solution of sodium
methylate. To this solution is added 0.18 ml (0.00275 mole) of
chloroethanol. The reaction mixture is heated at 40.degree. C. for 5
hours. 0.34 ml of 4N sodium methylate and 0.1 ml of chloroethanol are
added.
The mixture is maintained at 40.degree. C. overnight.
The pH of the reaction mixture is brought to 7.00 by the addition of dilute
hydrochloric acid.
The ethylene glycol is evaporated in a vacuum.
The residue after distillation is taken up in 6 ml of water and 5 ml of
concentrated hydrochloric acid, then stirred overnight at ambient
temperature.
The reaction mixture is concentrated then purified by preparative HPLC (RP
18, elution with water). After evaporation and drying, 0.1 g of product is
obtained in an overall yield (alkylation-purification) of 27%.
TLC (silica 60F254): CH.sub.2 Cl.sub.2 /methanol/7/3-Rf=0.33.
HPLC: column of Hypersil C8 5.mu. 25 cm
Buffer: 0.01M NaH.sub.2 PO.sub.4 /MeOH: 95/5
Purity: 95%
.sup.1 H NMR (Bruker-200 MHz) in DMSO: in conformity with the expected
structure.
EXAMPLE 5
Preparation of
5-[3-hydroxy-2-(hydroxymethyl)-propionamido]-N',N"-dimethyl]-bis-(2,3-dihy
droxypropyl)-2,4,6-triiodoisophtalamide.
a) Preparation of
[2-isopropyl-1,3-dioxanne-5-carboxamido]-N',N"-dimethyl-N',N"-bis-(2,3-dih
ydroxypropyl)-2,4,6-triiodoisophtalamide.
74 g (98 mmoles) of
5-[2-isopropyl-1,3-dioxanne-5-carboxamido]-2,4,6-triiodoisophtaloyle
dichloride are suspended in 300 ml of isopropanol containing 41 ml (294
mmoles) of triethylamine. 31 g (295 mmoles) of
N-methyl-aminopropane-2,3-diol are added dropwise. Stirring is maintained
12 h at room temperature. Triethylamine hydrochloride is removed by
filtration.
The filtrate is evaporated to dryness, taken up in water and eluted on
resin OH.sup.- IRA 67.
After evaporation, the product is purified on silanized silica (Kieselgel
60 Merck) with water as eluent.
After evaporation to dryness, 60 g of white powder are obtained with a
yield of 68.5%.
______________________________________
Purity in iodine: 96.4%
Purity HPLC: 97% Hypersil CB 25 cm 5 um
NaH.sub.2 PO.sub.4 0.01M
60
Methanol 40
TLC SiO.sub.2, Rf
0.12
0.25
0.30 0.36
Eluent CHCl.sub.3 55, MeOH 30, NH.sub.3 H.sub.2 O 10
______________________________________
RMN (DMSO) H 200 MHz: 0.9 ppm (d) CH.sub.3 (6H); 2.8 ppm (s) N--CH.sub.3
(3H); 3 ppm (s) N--CH.sub.3 (3H); 3.3 ppm (m) N--CH.sub.2 and CH (5H);
3.5-3.9 ppm (broad signal) CH.sub.2 et. CH (8H); 4.3 ppm (q) CH (3H); 4.6
ppm (t) OH (2H); 4.7 ppm (d) OH (2H); 10.2 ppm (broadened signal) NH (1H).
b) Preparation of
5-[3-hydroxy-2-(hydroxymethyl)-propionamido]-N',N"-dimethyl-N',N"-bis-(2,3
-dihydroxypropyl)-2,4,6-triiodoisophtalamide
45 g (50.6 mmole) of the compound disclosed in a) are dissolved in 101 ml
(10 eq) of hydrochloric acid 5N. Stirring is maintained 12 h at room
temperature. The solution is filtered and evaporated to dryness. The
resulting product is taken up in 100 ml of ethyl ether and then filtered
and eluted on silanized silica (Kieselgel 60 Merck) with water. After
evaporation to dryness, 38 g of white powder are obtained.
______________________________________
Yield = 90%
Purity in iodine = 98.3%
Purity HPLC > 98% Hypersil C8 25 cm 5 u
NaH.sub.2 PO.sub.4 0.01M
95
MeOH 5
TLC SiO.sub.2 Rf
0.56
0.63
0.67
Eluent CHCl.sub.3 55, MeOH 30, NH.sub.3, H.sub.2 O 10
______________________________________
RMN (DMSO) H 200 MHz: 2.7 ppm (broad signal) CH (1H); 2.85 ppm (broadened
singlet) N--CH.sub.3 (3H); 3.08 ppm (badly resolved doublet) N--CH.sub.3
(3H); 3.10-3.35 ppm (m) N--CH.sub.2 ; 3.45 ppm (q) CH.sub.2 (4H); 3.6-4
ppm (broad signal) OH (6H); 9.9 ppm (broad signal) NH (1H).
EXAMPLE 6
Preparation of
5-[3-hydroxy-2(hydroxymethyl)-N-(2,3-dihydroxypropyl)-propionamido]-N',N"-
dimethyl]-N',N"-bis(2-hydroxyethyl)-2,4,6-triiodoisophtalamide
a) Preparation of
5-[2-isopropyl-1,3-dioxanne-5-carboxamido]-N',N"-bis-(2-hydroxyethyl)-2,4,
6-triiodo isophtalamide
0.126 mole of the product obtained in example 1a are suspended in 400 ml of
isopropanol containing 53 ml of thriethylamine (0.378 m). 28.5 g (0.378 m)
of N-methyl amino ethanol are added dropwise. Stirring is maintained 16
hours at room temperature.
Triethylamine hydrochloride is removed by filtration. The filtrate is
evaporated to dryness and washed with 2.times.500 ml of water. The residue
is taken up in 600 ml of isopropanol and filtered on activated carbon. The
filtrate is concentrated to dryness and taken up in 600 ml of ethyl ether.
The precipitate is filtered and dried under vacuum.
Yield=82%
Purity HPLC=97%
TLC SiO.sub.2
Eluent CH.sub.2 Cl.sub.2 9, methanol 1
Rf=0.37, 0.33, 0.27.
b) Preparation of
5-[3-hydroxy-2(hydroxymethyl)-N-(2,3-dihydroxypropyl)-propionamido]-N',N"-
dimethyl]-N',N"-bis(2-hydroxyethyl)-2,4,6-triiodoisophtalamide
To a suspension of 20 g (0.0241 m) of the product obtained in 6a in 80 ml
of Monoglyme are added dropwise 25.3 g (0.145 m) of 30.8% (W/W) sodium
methylate at 35.degree. C. Stirring is maintained 1 hour at this
temperature.
16 g. of 1-chloro-2,3-propanediol (0.145 m) are added dropwise.
The mixture is maintained 24 hours at 35.degree. C. Mineral salts are
removed by filtration. Monoglyme is evaporated under vacuum. The
distillation residue is taken up in 100 ml of HCl 5N and is maintained
under stirring one night at room temperature. The reaction mixture is
concentrated to dryness. The oily residue is purified by preparative HPLC
(RP 18-elution by water and then water/methanol).
______________________________________
HPLC > 95% Hypersil CB 25cm 5.mu.
NaH.sub.2 PO.sub.4 0.01M
90
Methanol 10
1 ml/m
TLC SiO.sub.2, Rf 0.16, 0.21, 0.28, 0.36
Eluent water, acetic acid, butanol 25/11/5
______________________________________
RMN (DMSO) .sup.1 H.sup.13 C 200 MHz in accordance with the expected
structure.
Top